aRgus: Multilevel visualization of non-synonymous single nucleotide variants &amp; advanced pathogenicity score modeling for genetic vulnerability assessment

Schröter, Julian; Dattner, Tal; Hüllein, Jennifer; Jayme, Alejandra; Heuveline, Vincent; Hoffmann, Georg F.; Kölker, Stefan; Lenz, Dominic; Opladen, Thomas; Popp, Bernt; Schaaf, Christian P.; Staufner, Christian; Syrbe, Steffen; Uhrig, Sebastian; Hübschmann, Daniel; Brennenstuhl, Heiko

doi:10.1016/j.csbj.2023.01.027

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…Furthermore, to assess the predicted effect of missense variants, commonly used prediction scores (CADD v1.6, M‐CAP v.3.5a, REVEL v.3.5a21–23) were annotated for all biologically possible USP7 missense variants and mapped onto a linearized representation of the USP7 protein, as previously demonstrated 20 . A generalized additive model was built using the geom_smooth function of the R (R Core Team, Vienna, Austria) ggplot2 package to plot a smoothened line and confidence interval (Supplemental Figure 7).…”

Section: Resultsmentioning

confidence: 99%

“…Missense mutations were grouped based on functionally relevant protein regions. A mean value of 0.64 (n: 10) was found for the catalytic domain, 0.48 (n: 2) for the TRAF-like domain, and 0.41 (n: 8) for the UBL-like domain, reflecting a significantly increased severity score for mutations affecting the catalytic domain of USP7 (Figure 3C, p = 0.0041).Furthermore, to assess the predicted effect of missense variants, commonly used prediction scores (CADD v1.6, M-CAP v.3.5a, REVEL v.3.5a21-23) were annotated for all biologically possible USP7 missense variants and mapped onto a linearized representation of the USP7 protein, as previously demonstrated 20. A generalized additive model was built using the geom_smooth function of the R (R Core Team, Vienna, Austria) ggplot2 package to plot a smoothened line and confidence interval (Supplemental Figure7).…”

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confidence: 92%

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Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

Wimmer,

Brennenstuhl,

Hirsch

et al. 2024

Clinical Genetics

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Hao‐Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype–phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao‐Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome‐specific severity score. This score neither indicates a sex‐ nor age‐specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

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Section: Resultsmentioning

confidence: 99%

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confidence: 92%

Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

Wimmer,

Brennenstuhl,

Hirsch

et al. 2024

Clinical Genetics

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“…Given that heterozygous genotypes comprised two different variants, we calculated the mean, the maximum and the minimum of the two prediction scores for each genotype. Figure 1A,B comprised variant localizations and heat strip visualization of the REVEL score, were generated using the online tool aRgus 47 with modification. Tabular prediction score data for correlation analysis was also retrieved from the aRgus platform.…”

Section: Methodsmentioning

confidence: 99%

Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real‐world data

Yuan

Dimitrov

Boy

et al. 2023

J of Inher Metab Disea

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Glutaric aciduria type 1 (GA1) is caused by inherited deficiency of glutaryl-CoA dehydrogenase (GCDH). To further understand the unclear genotypephenotype correlation, we transfected mutated GCDH into COS-7 cells resembling known biallelic GCDH variants of 47 individuals with GA1. In total, we modeled 36 genotypes with 32 missense variants. Spectrophotometry demonstrated an inverse correlation between residual enzyme activity and the urinary concentration of glutaric acid and 3-hydroxyglutaric acid, confirming previous studies (Pearson correlation, r = À0.34 and r = À0.49, p = 0.045 and p = 0.002, respectively). In silico modeling predicted high pathogenicity for all genotypes, which caused a low enzyme activity. Western blotting revealed a 2.6-times higher GCDH protein amount in patients with an acute encephalopathic crisis (t-test, p = 0.015), and high protein expression correlated with high in silico protein stability (Pearson correlation, r = À0.42, p = 0.011). The protein amount was not correlated with the enzyme activity (Pearson correlation, r = 0.09, p = 0.59). To further assess protein stability, proteolysis was performed, showing that the p.Arg88Cys variant stabilized a heterozygous less stable variant. We conclude that an integration of different data sources helps to predict the complex clinical phenotype in individuals with GA1.

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“…Moreover, only exonic variants have been investigated by the presented modeling approach due to the applied technique of cloning the respective coding sequence into the expression vectors, which does not allow to assess the effect of intronic variants associated with defective splicing. Systematically integrating genotype‐specific in vitro residual enzymatic activities with the results of widely used in silico algorithm tools (such as aRgus 57 ) for multilevel visualization of single nucleotide variants and associated pathogenicity score modeling for vulnerability assessment with regard to protein structure, stability, and protein function might bare the potential of significantly improving risk stratification and phenotypic prediction in the future.…”

Section: From Bench To Bedside: Early Prediction Of Individual Diseas...mentioning

confidence: 99%

The challenge of understanding and predicting phenotypic diversity in urea cycle disorders

Posset,

Zielonka,

Gleich

et al. 2023

J of Inher Metab Disea

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The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long‐term follow‐up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease‐immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long‐term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.

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aRgus: Multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment

Cited by 7 publications

References 26 publications

Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real‐world data

The challenge of understanding and predicting phenotypic diversity in urea cycle disorders

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